Brentuximab vedotin and nivolumab alone and then combined with rituximab, cyclophosphamide, doxorubicin, and prednisone for frontline therapy of patients with primary mediastinal large B-cell lymphoma.
Authors: Raphael Eric Steiner, Paolo Strati, Christopher Flowers, Sattva Swarup Neelapu, Michael Richard Green, Loretta J. Nastoupil, Fredrick B. Hagemeister, Lei Feng, Sairah Ahmed, Ranjit Nair, Luis Fayad, Hun Ju Lee, Maria Alma Rodriguez, Jason Westin
Journal: Journal of Clinical Oncology (2022)

TPS7589 Background: Primary mediastinal large B-cell lymphoma (PMBL) is a rare and distinct subtype of diffuse large B-cell lymphoma and affects primarily young adults. PMBL has a unique genomic profile that has similarities to classic Hodgkin lymphoma with CD30 expression and genomic alterations in the programmed T-cell death-ligand 1 (PD-L1) locus 9p24.1. The trial CheckMate-436, including relapsed/refractory PMBL patients treated with nivolumab (antibody that binds to immune checkpoint PD-1) and brentuximab vedotin ((BV) anti-CD30 antibody-drug conjugate) showed an overall response rate (ORR) of 73% and complete response rate (CRR) of 43% (Zinzani et al. JCO 2019). Although most PMBL patients can be cured with frontline chemoimmunotherapy with or without radiotherapy, the outcome of patients having rr-PMBL treated with intensive regimens is generally unfavorable. The discovery of new frontline regimens to decrease chemoresistance and toxicities represents an urgent unmet clinical need for PMBL patients. Methods: We are conducting a phase II, open-label, single-center clinical trial combining BV-Nivolumab alone and then combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for patients with previously untreated PMBL Patients 18 years or older with previously untreated PMBL, stage I to stage IV disease are eligible. However, patients with an urgent need for cytoreductive treatment will be excluded. Patients will receive BV 1.8 mg/Kg IV and Nivolumab 240 mg flat dose IV day 1 for cycles 1 and 2, in a 21-day cycle. During cycles 3 and 4, R-CHP will be added to BV-Nivolumab. Patients who have achieved complete response (CR) at PET/CT before cycle 5 will receive 2 more cycles of BV-Nivolumab+R-CHP (cycle 5 and 6) and BV-Nivolumab only for cycles 7 and 8. In case of CR on PET/CT after cycle 8, therapy will be considered completed. Patients in PR on PET/CT before cycle 5 will receive 4 more cycles of BV-Nivolumab+R-CHP (cycles 5-8). The primary endpoint is CRR at the end of therapy (EOT). The maximum sample size for the PMBL cohort is 40 patients, with a target CRR at EOT of 70%. The null hypothesis is that the true CRR at EOT is 50%, and the alternative hypothesis is that the true CRR at EOT is 70%. The Simon’s optimal two-stage design controls the one-sided type I error rate at 0.06 and yields the power of 0.8. The secondary endpoints will include the response rate of BV-Nivolumab+R-CHP at the end of the immune lead-in, landmark survival outcomes, the safety of the combination, and patient-reported outcome. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and Multiplexed ion beam imaging to analyze the tumor microenvironment. The trial is actively accruing at MD Anderson Cancer Center, and 2 out of 40 patients have been enrolled. Clinical trial information: NCT04745949.